JP2003012672A - Method for producing growth hormone secretagogue and intermediate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a specific hormone secretagogue and an intermediate capable of being used in the method. SOLUTION: This method for producing a compound of formula VI, comprises reacting a compound of formula IV with a carbonyl equivalent and CF3 CH2 NH2 in a reaction inert solvent to form a compound of formula VII, reacting the compound of formula VII with 2-picolyl-Z<1> in the presence of a base and a reaction inert solvent at about -78 deg.C to about 25 deg.C for about 1 hr to about 24 hr to form a compound of formula VIII, reacting the compound of formula VIII with a suitable acid in a reaction inert solvent at about -30 deg.C to about 25 deg.C for about 1 hr to about 10 hr to form a compound of formula IX, resolving the compound of formula IX with D-tartaric acid in a reaction inert solvent to form the D-tartrate salt of a compound of formula X, reacting the D-tartrate salt of a compound of formula X with a compound of formula XI, a peptide coupling reagent and a base in a reaction inert solvent to form a compound of formula XII and reacting the compound of formula XII under standard t- butyloxycarbonyl group removing conditions to form a compound of formula VI.

Description

Detailed Description of the Invention

[0001]

This invention relates to compounds of formula I

[0002]

[Chemical 20]

(Wherein R ¹ , R ² and Pt are as defined below), the compound being used for the production of a specific growth hormone secretagogue of formula II: You can The present invention also relates to a method for producing the growth hormone secretagogue.

[0004]

The compounds of formula II in which R ¹ and R ² are as defined below are potent growth hormone secretagogues. These compounds and their preparation are disclosed in US Provisional Patent Application No. 60 / 050,764.

[0005]

[Chemical 21]

[0006]

The present invention is directed to compounds of formula VII:

[0007]

[Chemical formula 22]

(Where Pt is an amine protecting group.) Preferred compounds of formula VII are those in which Pt is Boc. The present invention also provides a method designated as Method A for preparing a compound of formula III:

[0009]

[Chemical formula 23]

(Where Pt is an amine protecting group; R
²Is hydrogen, (C₁-C₈) Alkyl,-(C₀-C₃) Al
Kill- (C₃-C₈) Cycloalkyl,-(C₁-C_Four)
Rukiru-A¹Or A¹And each A¹Is (C_Five−
C₇) Cycloalkenyl: phenyl: oxygen, sulfur and
1 to 4 independently selected from the group consisting of nitrogen
Partially saturated, fully saturated, which may have terror atoms
Summed or fully unsaturated 4- to 8-membered rings: and
Independently selected from the group consisting of nitrogen, sulfur and oxygen
Partly optionally having 1 to 4 heteroatoms
5 if saturated, fully saturated, or completely unsaturated
From nitrogen, sulfur and oxygen fused to a 6-membered ring
1 to 4 heteroatoms independently selected from the group
May be partially saturated, fully unsaturated,
Or a bicyclic, fully saturated 5- or 6-membered ring
Independently selected from the group consisting of ring systems; each A¹Is A¹
Is a bicyclic ring system, one ring or optionally
Where both rings are independently substituted with up to 3 substituents
Each substituent may be F, Cl, Br, I or OC.
F₃, OCF₂H, CF₃, CH₃, OCH₃, -OX⁶,-
C (O) N (X⁶) (X⁶), -C (O) OX⁶, Oki
So, (C₁-C₆) Alkyl, nitro, cyano, benzyl
Le, -S (O)_m(C₁-C₆) Alkyl, 1H-tetra
Zol-5-yl, phenyl, phenoxy, phenylal
Killoxy, halophenyl, methylenedioxy, -N
(X⁶) (X⁶), -N (X⁶) C (O) (X⁶), -S
(O)₂N (X⁶) (X⁶), -N (X⁶) S (O)₂-F
Phenyl, -N (X⁶) S (O)₂X⁶, -CONX
¹¹X¹², -S (O)₂NX¹¹X¹², -NX⁶S (O)₂X
¹², -NX⁶CONX¹¹X¹², -NX⁶S (O)₂NX¹¹
X¹², -NX⁶C (O) X¹², Imidazolyl, thiazoly
Independently selected from the group consisting of
Dashi A¹Is optionally substituted with methylenedioxy
In that case only substituted with one methylenedioxy
Yes; X here¹¹May be hydrogen or substituted
I (C₁-C₆) Alkyl; X¹¹Is defined about
Which may be substituted (C₁-C₆) Alkyl is German
Vertically, phenyl, phenoxy, (C₁-C₆) Alkoxy
Carbonyl, -S (O)_m(C₁-C₆) Alkyl, 1
5 halo groups, 1 to 3 hydroxy groups, 1
Three stones (C₁-C_Ten) Alkanoyloxy group or 1
To 3 (C₁-C₆) Is substituted with an alkoxy group
May be; X¹²Is hydrogen, (C₁-C₆) Alkyl, pheny
, Thiazolyl, imidazolyl, furyl or thienyl
Yes, but X¹²X is not hydrogen¹²The base is C
l, F, CH₃, OCH₃, OCF₃And CF₃A group of
Substituted with 1 to 3 substituents more independently selected
Or X¹¹And X¹²Together with-(CH₂)_r
-L¹-(CH₂)_r-Forms; L¹Is C (X²)
(X²), O, S (O)_mOr N (X²) Is each;
Each X⁶Are independently hydrogen or optionally substituted (C₁
-C₆) Alkyl, (C₂-C₆) Alkyl halides,
May be substituted (C₃-C₇) Cycloalkyl,
(C₃-C₇) Is a cycloalkyl halide, where
X⁶May be substituted in the definition of (C₁-C₆)
Alkyl and optionally substituted (C ₃-C₇) Cyclo
Alkyl is independently (C₁-C_Four) Alkyl, hydroxy
Shi, (C ₁-C_Four) Alkoxy, carboxyl, CONH
₂, -S (O)_m(C₁-C₆) Alkyl, carboxylic acid (C
₁-C_Four) Alkyl ester or 1H-tetrazol-5
Optionally mono- or di-substituted with yl;
Two Xs on an atom⁶A group exists and both X⁶Independently
(C₁-C₆) Alkyl, the two (C₁−
C₆) The alkyl group is bonded to form the two X⁶Groups are bound
Oxygen, sulfur or NX with atoms⁷The ring component
May form a 4- to 9-membered ring which may have
Each r is independently 1, 2 or 3. )following
Compound of formula IV

[0011]

[Chemical formula 24]

(Wherein R ³ is (C ₁ -C ₄ ) alkyl and Pt is as defined above) with a preformed isocyanate or carbonyl equivalent and R
² NH ₂ (where R ² is as defined above) in a reaction inert solvent for about 1 hour to about 72 hours at about 0 ° C.
To a method comprising reacting at a temperature of from about 80 ° C.

Preferred within the scope of Method A, designated Method B.
The new way is R²Is hydrogen, (C₁-C ₈) Alkyl or-
(C₀-C₃) Alkyl- (C₃-C₈) With cycloalkyl
Yes; R²And cycloalkyl in the definition of
Even if the radical is substituted with 1, 2 or 3 fluorines
Well, and Pt is tert-butyloxycarbonyl
Including a method.

A preferred method within the scope of Method B, designated Method C, comprises reacting a compound of formula IV above with a carbonyl equivalent selected from carbonyldiimidazole, phosgene, triphosgene and diphosgene.

Preferred methods within the scope of Method C, designated Method D, include those wherein said carbonyl equivalent is carbonyldiimidazole and said reaction inert solvent is methylene chloride.

Preferred methods within the scope of Method D, designated Method E, include those wherein R ² is methyl, ethyl or 2,2,2-trifluoroethyl. A particularly preferred method within the scope of Method E is where R ² is methyl.

Another particularly preferred method within the scope of Method E is the method wherein R ² is ethyl. Further, the present invention is
A method designated as Method F for preparing a compound of formula I:

[0018]

[Chemical 25]

(Where R¹Is-(CH₂)_qN (X⁶) C
(O) X⁶,-(CH₂)_qN (X⁶) C (O) (CH₂)_t
-A¹,-(CH₂)_qN (X⁶) S (O)₂(CH₂)_t−
A¹,-(CH₂)_qN (X⁶) S (O)₂X⁶,-(C
H₂)_qN (X⁶) C (O) N (X⁶) (CH₂)_t-A¹,
-(CH₂)_qN (X⁶) C (O) N (X⁶) (X⁶),-
(CH₂)_qC (O) N (X⁶) (X⁶),-(CH₂)_qC
(O) N (X⁶) (CH₂)_t-A¹,-(CH₂)_qC
(O) OX⁶,-(CH₂)_qC (O) O (CH₂)_t−
A¹,-(CH ₂)_qOX⁶,-(CH₂)_qOC (O)
X⁶,-(CH₂)_qOC (O) (CH₂)_t-A¹,-(C
H₂)_qOC (O) N (X⁶) (CH₂)_t-A¹,-(CH
₂)_qOC (O) N (X⁶) (X⁶),-(CH₂)_qC
(O) X⁶,-(CH₂)_qC (O) (CH₂)_t-A¹,-
(CH₂)_qN (X⁶) C (O) OX⁶,-(CH₂)_qN
(X⁶) S (O)₂N (X⁶) (X⁶),-(CH₂)_qS
(O)_mX⁶,-(CH₂)_qS (O)_m(CH₂)_t-A¹,
-(C₁-C_Ten) Alkyl,-(CH₂)_q-A¹,-(C
H₂) _q-(C₃-C₇) Cycloalkyl,-(CH₂)_q−
Y¹-(C₁-C₆) Alkyl,-(CH₂)_q-Y¹-(C
H₂)_t-A¹Or- (CH₂)_q-Y¹-(CH₂)_t−
(C₃-C₇) Cycloalkyl; where R¹Fixed
The alkyl and cycloalkyl groups in the meaning are (C₁−
C_Four) Alkyl, hydroxy, (C₁-C_Four) Arkoki
Si, carboxyl, -CONH₂, -S (O)_m(C₁−
C₆) Alkyl, -CO₂(C₁-C_Four) Alkyl Esthe
1H-tetrazol-5-yl or 1, 2 or 3
Optionally substituted with 4 fluoro groups; Y¹Is O, S
(O)_m, -C (O) NX⁶-, -CH = CH-, -C≡
C-, -N (X⁶) C (O)-, -C (O) NX⁶-,-
C (O) O-, -OC (O) N (X⁶)-Or -OC
(O)-; q is 1, 2, 3 or 4; t is
0, 1, 2 or 3; R¹In the definition of (C
H₂)_qGroup and (CH₂)_tThe groups are independently hydroxy,
(C₁-C_Four) Alkoxy, carboxyl, -CON
H₂, -S (O)_m(C₁-C₆) Alkyl, -CO₂(C₁
-C_Four) Alkyl ester, 1H-tetrazol-5-a
1, 2, or 3 fluoro groups or 1 or 2
Of (C₁-C_Four) May be substituted with an alkyl group;
And R²Is hydrogen, (C₁-C₈) Alkyl,-(C₀-C
₃) Alkyl- (C₃-C₈) Cycloalkyl,-(C₁−
C_Four) Alkyl-A¹Or A¹And where R¹Definition of
The alkyl group and cycloalkyl group in
Si, -C (O) OX⁶, -C (O) N (X⁶) (X⁶),
-N (X⁶) (X⁶), -S (O)_m(C₁-C₆) Archi
Le, -C (O) A¹, -C (O) (X⁶), CF₃, CN
Or with 1, 2 or 3 independently selected halo groups
May be replaced; each A¹Is (C_Five-C₇) Shiku
Lower alkenyl: phenyl: consisting of oxygen, sulfur and nitrogen
1 to 4 heteroatoms independently selected from the group
May have partially saturated, fully saturated, if
Or a fully unsaturated 4- to 8-membered ring: as well as nitrogen, io
1 to 4 independently selected from the group consisting of c and oxygen
Partially saturated, optionally having 4 heteroatoms,
Fully saturated or completely unsaturated 5- or 6-membered ring
From the group consisting of nitrogen, sulfur and oxygen fused to
Having 1 to 4 independently selected heteroatoms
May be partially saturated, completely unsaturated, or completely
Consists of a bicyclic ring system consisting of fully saturated 5- or 6-membered rings
Selected independently from each group; each A¹Is A¹Is a bicyclic ring
One ring if system, or both, as the case may be
The ring of may be independently substituted with up to 3 substituents
And each substituent is F, Cl, Br, I, OCF.₃, O
CF₂H, CF₃, CH₃, OCH₃, -OX⁶, -C
(O) N (X⁶) (X⁶), -C (O) OX⁶, Oxo,
(C₁-C₆) Alkyl, nitro, cyano, benzyl,-
S (O)_m(C₁-C₆) Alkyl, 1H-tetrazole-
5-yl, phenyl, phenoxy, phenyl alkylo
Xy, halophenyl, methylenedioxy, -N (X⁶)
(X⁶), -N (X⁶) C (O) (X⁶), -S (O)₂N
(X⁶) (X⁶), -N (X⁶) S (O)₂-Phenyl,-
N (X⁶) S (O)₂X⁶, -CONX¹¹X¹², -S
(O)₂NX¹¹X¹², -NX⁶S (O)₂X¹², -NX⁶C
ONX¹¹X¹², -NX⁶S (O)₂NX¹¹X¹², -NX⁶
C (O) X¹², Imidazolyl, thiazolyl and tetrazo
Independently selected from the group consisting of Lil, where A¹Is meth
When it may be substituted with dioxy, one
It can only be replaced with tolylenedioxy;
X here¹¹Is hydrogen or optionally substituted (C₁-C₆)
Alkyl; X¹¹Is defined as the permuted
May be (C₁-C₆) Alkyl independently represents phenyl
Le, phenoxy, (C₁-C₆) Alkoxycarbonyl,
-S (O)_m(C₁-C₆) Alkyl, 1 to 5 ha
B group, 1 to 3 hydroxy groups, 1 to 3
(C₁-C_Ten) Alkanoyloxy groups or 1 to 3
Of (C₁-C₆) May be substituted with an alkoxy group;
X¹²Is hydrogen, (C₁-C₆) Alkyl, phenyl, thiazo
Ril, imidazolyl, furyl or thienyl, only
X¹²X is not hydrogen¹²Groups are Cl, F, CH
₃, OCH₃, OCF₃And CF₃Independently selected from the group consisting of
May be substituted with 1 to 3 substituents selected
Or X¹¹And X¹²Together with-(CH₂)_r-L¹−
(CH₂)_r-Forms; L¹Is C (X²) (X²), O,
S (O)_mOr N (X²); Each X⁶Is German
By the way, hydrogen may be substituted (C₁-C₆) Archi
Le, (C₂-C₆) Alkyl halides, substituted
Good (C₃-C₇) Cycloalkyl, (C₃-C₇)Halo
A cycloalkyl genide, where X⁶In the definition of
May be substituted (C₁-C₆) Alkyl and substitution
May be (C ₃-C₇) Cycloalkyl is independent
, (C₁-C_Four) Alkyl, hydroxy, (C ₁-C_Four)
Alkoxy, carboxyl, CONH₂, -S (O)
_m(C₁-C₆) Alkyl, carboxylic acid (C₁-C_Four) Al
Kill ester or 1H-tetrazol-5-yl
Or may be disubstituted; or two per atom.
X⁶A group exists and both X⁶Independently (C₁-C₆)
If it is a rukill, the two (C₁-C₆) The alkyl group is
Combined, the two X⁶Acid, along with the atom to which the group is attached
Elemental, sulfur or NX⁷As a ring component
May optionally form a 4- to 9-membered ring; each r is
Independently 1, 2 or 3; each X²Is independent
To hydrogen, which may be substituted (C₁-C₆) Alkyl
Or may be substituted (C₃-C₇) Cycloalkyl
And where X²May be substituted in the definition of
I (C₁-C₆) Alkyl and optionally substituted (C
₃-C₇) Cycloalkyl is independently -S (O)._m(C₁
-C₆) Alkyl, -C (O) OX³1 to 5 c
B group or 1-3 OXs³May be substituted with a group
Each X³Are independently hydrogen or (C₁-C₆) Al
It ’s a kill; X⁷Is substituted with hydrogen or hydroxy
May be (C₁-C₆) Alkyl; each m is
Independently 0, 1 or 2; provided that X is⁶And X⁷Is
C (O) X⁶, C (O) X¹², S (O)₂X⁶Or S
(O)₂X¹²In the form of C (O) or S (O)₂Join to
May not be hydrogen; as well as Pt is an amine protecting group
Is. ) Compound of formula III

[0020]

[Chemical formula 26]

(Where Pt and R ² are as defined above) is represented by the formula R ¹ -Z where R ¹ is as defined above and Z is a leaving group. Of an alkylating agent according to claim 1) in the presence of a suitable base and a reaction inert solvent.

Within the scope of Method F, which is named Method G
The preferred method is R¹Is-(CH₂) _q-A¹Or (C₁−
C₇) Alkyl; and R²Is hydrogen, (C₁-C₈)
Rukiru or-(C₀-C₃) Alkyl- (C₃-C₈) Shiku
A method which is a lower alkyl; wherein R is²To the definition of
1, 2 or 3 alkyl and cycloalkyl groups
May be substituted with fluorine, and Pt is tert.
-Butyloxycarbonyl.

A preferred method within the scope of Method G, designated Method H, is where in the alkylating agent Z is p-toluenesulfonyloxy, methanesulfonyloxy or halo; and the base is an alkali metal bis (trimethylsilyl). An amide or an alkali alkoxide; and the reaction inert solvent is N, N-dimethylformamide,
Including tetrahydrofuran, toluene, isopropyl ether, MTBE or mixtures thereof.

Within the scope of Method H, designated Method I
The preferred method is R¹Is -CH₂-A ¹And Z is C
l, Br or I, and R²Is hydrogen or 1, 2 or
It may be substituted with three fluoro groups (C₁-C₃)
Including methods that are alkyl.

A preferred method within the scope of Method I, designated Method J, is where A ¹ is phenyl, pyridyl or thiazolyl optionally substituted with 1 to 3 substituents, each substituent being Is F, Cl, CH ₃ , OCF ₂ H, O
Independently selected from the group consisting of CF ₃ and CF ₃ ; and R
² is methyl, ethyl or 2,2,2-trifluoroethyl.

A particularly preferred method within the scope of Method J is where R ¹ is pyridin-2-ylmethyl or benzyl, which benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl groups; And R ² is methyl.

Another particularly preferred method within the scope of Method J is that R ¹ is pyridin-2-ylmethyl or benzyl, which benzyl is substituted with up to two fluoro, chloro or trifluoromethyl. Well; and R
^The method in which ² is ethyl.

Yet another particularly preferred method within the scope of Method J is where R ¹ is pyridin-2-ylmethyl or benzyl, which benzyl is substituted with up to two fluoro, chloro or trifluoromethyl. May;
And R ² is 2,2,2-trifluoroethyl.

The present invention also provides a method designated as Method K for preparing a compound of formula V:

[0030]

[Chemical 27]

(Where R¹Is-(CH₂)_qN (X⁶) C
(O) X⁶,-(CH₂)_qN (X⁶) C (O) (CH₂)_t
-A¹,-(CH₂)_qN (X⁶) S (O)₂(CH₂)_t−
A¹,-(CH₂)_qN (X⁶) S (O)₂X⁶,-(C
H₂)_qN (X⁶) C (O) N (X⁶) (CH₂)_t-A¹,
-(CH₂)_qN (X⁶) C (O) N (X⁶) (X⁶),-
(CH₂)_qC (O) N (X⁶) (X⁶),-(CH₂)_qC
(O) N (X⁶) (CH₂)_t-A¹,-(CH₂)_qC
(O) OX⁶,-(CH₂)_qC (O) O (CH₂)_t−
A¹,-(CH ₂)_qOX⁶,-(CH₂)_qOC (O)
X⁶,-(CH₂)_qOC (O) (CH₂)_t-A¹,-(C
H₂)_qOC (O) N (X⁶) (CH₂)_t-A¹,-(CH
₂)_qOC (O) N (X⁶) (X⁶),-(CH₂)_qC
(O) X⁶,-(CH₂)_qC (O) (CH₂)_t-A¹,-
(CH₂)_qN (X⁶) C (O) OX⁶,-(CH₂)_qN
(X⁶) S (O)₂N (X⁶) (X⁶),-(CH₂)_qS
(O)_mX⁶,-(CH₂)_qS (O)_m(CH₂)_t-A¹,
-(C₁-C_Ten) Alkyl,-(CH₂)_q-A¹,-(C
H₂) _q-(C₃-C₇) Cycloalkyl,-(CH₂)_q−
Y¹-(C₁-C₆) Alkyl,-(CH₂)_q-Y¹-(C
H₂)_t-A¹Or- (CH₂)_q-Y¹-(CH₂)_t−
(C₃-C₇) Cycloalkyl; where R¹Fixed
The alkyl and cycloalkyl groups in the meaning are (C₁−
C_Four) Alkyl, hydroxy, (C₁-C_Four) Arkoki
Si, carboxyl, -CONH₂, -S (O)_m(C₁−
C₆) Alkyl, -CO₂(C₁-C_Four) Alkyl Esthe
1H-tetrazol-5-yl or 1, 2 or 3
Optionally substituted with 4 fluoro groups; Y¹Is O, S
(O)_m, -C (O) NX⁶-, -CH = CH-, -C≡
C-, -N (X⁶) C (O)-, -C (O) NX⁶-,-
C (O) O-, -OC (O) N (X⁶)-Or -OC
(O)-; q is 1, 2, 3 or 4; t is
0, 1, 2 or 3; R¹In the definition of (C
H₂)_qGroup and (CH₂)_tThe groups are independently hydroxy,
(C₁-C_Four) Alkoxy, carboxyl, -CON
H₂, -S (O)_m(C₁-C₆) Alkyl, -CO₂(C₁
-C_Four) Alkyl ester, 1H-tetrazol-5-a
1, 2, or 3 fluoro groups or 1 or 2
Of (C₁-C_Four) May be substituted with an alkyl group;
And R²Is hydrogen, (C₁-C₈) Alkyl,-(C₀-C
₃) Alkyl- (C₃-C₈) Cycloalkyl,-(C₁−
C_Four) Alkyl-A¹Or A¹And where R¹Definition of
The alkyl group and cycloalkyl group in
Si, -C (O) OX⁶, -C (O) N (X⁶) (X⁶),
-N (X⁶) (X⁶), -S (O)_m(C₁-C₆) Archi
Le, -C (O) A¹, -C (O) (X⁶), CF₃, CN
Or with 1, 2 or 3 independently selected halo groups
May be replaced; each A¹Is (C_Five-C₇) Shiku
Lower alkenyl: phenyl: consisting of oxygen, sulfur and nitrogen
1 to 4 heteroatoms independently selected from the group
May have partially saturated, fully saturated, if
Or a fully unsaturated 4- to 8-membered ring: as well as nitrogen, io
1 to 4 independently selected from the group consisting of c and oxygen
Partially saturated, optionally having 4 heteroatoms,
Fully saturated or completely unsaturated 5- or 6-membered ring
From the group consisting of nitrogen, sulfur and oxygen fused to
Having 1 to 4 independently selected heteroatoms
May be partially saturated, completely unsaturated, or completely
Consists of a bicyclic ring system consisting of fully saturated 5- or 6-membered rings
Selected independently from each group; each A¹Is A¹Is a bicyclic ring
One ring if system, or both, as the case may be
The ring of may be independently substituted with up to 3 substituents
And each substituent is F, Cl, Br, I, OCF.₃, O
CF₂H, CF₃, CH₃, OCH₃, -OX⁶, -C
(O) N (X⁶) (X⁶), -C (O) OX⁶, Oxo,
(C₁-C₆) Alkyl, nitro, cyano, benzyl,-
S (O)_m(C₁-C₆) Alkyl, 1H-tetrazole-
5-yl, phenyl, phenoxy, phenyl alkylo
Xy, halophenyl, methylenedioxy, -N (X⁶)
(X⁶), -N (X⁶) C (O) (X⁶), -S (O)₂N
(X⁶) (X⁶), -N (X⁶) S (O)₂-Phenyl,-
N (X⁶) S (O)₂X⁶, -CONX¹¹X¹², -S
(O)₂NX¹¹X¹², -NX⁶S (O)₂X¹², -NX⁶C
ONX¹¹X¹², -NX⁶S (O)₂NX¹¹X¹², -NX⁶
C (O) X¹², Imidazolyl, thiazolyl and tetrazo
Independently selected from the group consisting of Lil, where A¹Is meth
When it may be substituted with dioxy, one
It can only be replaced with tolylenedioxy;
X here¹¹Is hydrogen or optionally substituted (C₁-C₆)
Alkyl; X¹¹Is defined as the permuted
May be (C₁-C₆) Alkyl independently represents phenyl
Le, phenoxy, (C₁-C₆) Alkoxycarbonyl,
-S (O)_m(C₁-C₆) Alkyl, 1 to 5 ha
B group, 1 to 3 hydroxy groups, 1 to 3
(C₁-C_Ten) Alkanoyloxy groups or 1 to 3
Of (C₁-C₆) May be substituted with an alkoxy group;
X¹²Is hydrogen, (C₁-C₆) Alkyl, phenyl, thiazo
Ril, imidazolyl, furyl or thienyl, only
X¹²X is not hydrogen¹²Groups are Cl, F, CH
₃, OCH₃, OCF₃And CF₃Independently selected from the group consisting of
May be substituted with 1 to 3 substituents selected
Or X¹¹And X¹²Together with-(CH₂)_r-L¹−
(CH₂)_r-Forms; L¹Is C (X²) (X²), O,
S (O)_mOr N (X²); Each X⁶Is German
By the way, hydrogen may be substituted (C₁-C₆) Archi
Le, (C₂-C₆) Alkyl halides, substituted
Good (C₃-C₇) Cycloalkyl, (C₃-C₇)Halo
A cycloalkyl genide, where X⁶In the definition of
May be substituted (C₁-C₆) Alkyl and substitution
May be (C ₃-C₇) Cycloalkyl is independent
, (C₁-C_Four) Alkyl, hydroxy, (C ₁-C_Four)
Alkoxy, carboxyl, CONH₂, -S (O)
_m(C₁-C₆) Alkyl, carboxylic acid (C₁-C_Four) Al
Kill ester or 1H-tetrazol-5-yl
Or may be disubstituted; or two per atom.
X⁶A group exists and both X⁶Independently (C₁-C₆)
If it is a rukill, the two (C₁-C₆) The alkyl group is
Combined, the two X⁶Acid, along with the atom to which the group is attached
Elemental, sulfur or NX⁷As a ring component
May optionally form a 4- to 9-membered ring; each r is
Independently 1, 2 or 3; each X²Is independent
To hydrogen, which may be substituted (C₁-C₆) Alkyl
Or may be substituted (C₃-C₇) Cycloalkyl
And where X²May be substituted in the definition of
I (C₁-C₆) Alkyl and optionally substituted (C
₃-C₇) Cycloalkyl is independently -S (O)._m(C₁
-C₆) Alkyl, -C (O) OX³1 to 5 c
B group or 1-3 OXs³May be substituted with a group
Each X³Are independently hydrogen or (C₁-C₆) Al
It ’s a kill; X⁷Is substituted with hydrogen or hydroxy
May be (C₁-C₆) Alkyl; each m is
Independently 0, 1 or 2; provided that X is⁶And X⁷Is
C (O) X⁶, C (O) X¹², S (O)₂X⁶Or S
(O)₂X¹²In the form of C (O) or S (O)₂Join to
In some cases it cannot be hydrogen. ) Compound of formula I

[0032]

[Chemical 28]

A method comprising reacting (where Pt is an amine protecting group and R ¹ and R ² are as defined above) with an acid in the presence of a reaction inert solvent. Is also directed.

Within the scope of Method K, which is named Method L
The preferred method is R¹Is-(CH₂) _q-A¹Or (C₁−
C₇) Alkyl; and R²Is hydrogen, (C₁-C₈)
Rukiru or-(C₀-C₃) Alkyl- (C₃-C₈) Shiku
A method which is a lower alkyl; wherein R is²To the definition of
1, 2 or 3 alkyl and cycloalkyl groups
Of fluorine, and Pt is t-butyl.
It is luoxycarbonyl.

Within the scope of Method L, named Method M
The preferred method is that the acid is methanesulfonic acid,
And the reaction inert solvent is methylene chloride.
Mu. Preferred within the scope of Method M, designated Method N
The method is R¹Is -CH₂-A ¹And R²Is hydrogen or
May be substituted with 1, 2 or 3 fluoro groups
I (C₁-C₃) Alkyl is included.

Within the scope of Method N, named Method O
The preferred method is R¹Is -CH₂-A ¹And where A¹
Is phenyl optionally substituted with 1 to 3 substituents
Or pyridyl or thiazolyl, each substituent being
F, Cl, CH₃, OCF₂H, OCF₃And CF₃Empty
Independently selected from the group; and R²Is methyl, ethyl or
Includes 2,2,2-trifluoroethyl.

A particularly preferred method within the scope of Method O is where R ¹ is pyridin-2-ylmethyl or benzyl, which benzyl may be substituted with up to two fluoro, chloro or trifluoromethyl. , Especially where the benzyl is substituted with up to ² fluoros; and R ² is methyl. Even more preferred within the scope of this method is where R ¹ is benzyl and R ²
Is methyl, or R ¹ is pyridin-2-ylmethyl and R ² is methyl.

Another particularly preferred method within the scope of Method O is that R ¹ is pyridin-2-ylmethyl or benzyl, which benzyl is substituted with up to two fluoro, chloro or trifluoromethyl. Well; and R
^The method in which ² is ethyl. Even more preferred within the scope of this method is the method wherein R ¹ is benzyl and R ² is ethyl, or R ¹ is pyridin-2-ylmethyl and R ² is ethyl.

Yet another particularly preferred method within the scope of Method O is where R ¹ is pyridin-2-ylmethyl or benzyl, which benzyl is substituted with up to two fluoro, chloro or trifluoromethyl. May;
And R ² is 2,2,2-trifluoroethyl. Even more preferred within the scope of this method is the method wherein R ¹ is benzyl and R ² is trifluoroethyl, or R ¹ is pyridin-2-ylmethyl and R ² is trifluoroethyl. Is.

The present invention also provides a method designated as Method P for preparing a compound of formula XIII:

[0041]

[Chemical 29]

(A) Piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3- (C ₁ -C ₄ ) alkyl ester is reacted with carbonyl equivalent and 2,2,2- in the presence of a reaction inert solvent. Reacting with trifluoroethylamine to form a compound of formula XIV:

[0043]

[Chemical 30]

(B) The compound of formula XIV is treated with 2-picolyl-Z ¹ (wherein Z ¹ is halo, methanesulfonyloxy or p-toluenesulfonyloxy) in the presence of a base and a reaction inert solvent. The following formula XV
Forming a compound of

[0045]

[Chemical 31]

(C) It is also directed to a method comprising reacting the compound of formula XV with an acid in the presence of a reaction inert solvent. A preferred method within the scope of Method P, designated Method Q, is that in step (a) the carbonyl equivalent is N, N′-carbonyldiimidazole, phosgene, diphosgene or triphosgene and the reaction inert solvent is Is methylene chloride; in step (b), the alkylating agent is 2-picolyl chloride and the base is potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, sodium amide, potassium amide, sodium (C ₁ -C ₄₎ alkoxide or potassium (C ₁ -C ₄₎ an alkoxide,
And the reaction inert solvent is tetrahydrofuran and N,
A mixed solution of N-dimethylformamide; and in the step (c), the acid is methanesulfonic acid,
And the reaction inert solvent is methylene chloride.

A preferred method within reaction Q is that in step (a) the carbonyl equivalent is N, N'-
Carbonyldiimidazole; and step (b)
In, the acid is potassium bis (trimethylsilyl)
The method is amide.

The present invention also provides a method designated as Method R for preparing a compound of formula VI:

[0049]

[Chemical 32]

(A) Compound of the following formula IV

[0051]

[Chemical 33]

(Where Pt is an amine protecting group and R ³ is (C ₁ -C ₄ ) alkyl) is reacted with a carbonyl equivalent and CF ₃ CH ₂ NH ₂ in a reaction inert solvent. To form a compound of formula VII:

[0053]

[Chemical 34]

(Where Pt is as defined above). (B) The compound of formula VII is treated with 2-picolyl-Z ¹ (wherein
Z ¹ is halo, methanesulfonyloxy or p-toluenesulfonyloxy) in the presence of a base and a reaction inert solvent at a temperature of about −78 ° C. to about 25 ° C. for about 1 hour to about 24 hours. To form a compound of formula VIII:

[0055]

[Chemical 35]

(Pt is as defined above.) (C) The compound of formula VIII is reacted with a suitable acid in a reaction inert solvent at a temperature of about -30 ° C to about 25 ° C. Reacting for about 1 hour to about 10 hours to form a compound of formula IX:

[0057]

[Chemical 36]

(D) The compound of formula IX is separated with D-tartaric acid in a reaction-inert solvent to give D- of the compound of formula X below.
Forms tartrate,

[0059]

[Chemical 37]

(E) The D-tartrate salt of the compound of formula X is reacted with a compound of formula XI

[0061]

[Chemical 38]

(Here, Boc is tert-butyloxycarbonyl). By reacting with a peptide coupling agent and a base, the following formula XI
Forming a compound of I,

[0063]

[Chemical Formula 39]

And (f) reacting the compound of formula XII under standard t-butyloxycarbonyl group removal conditions to form a compound of formula VI:

[0065]

[Chemical 40]

It is also directed to a method including: A preferred method within the scope of Method R, designated as Method S, is that in step (a) said carbonyl equivalent is N, N′-carbonyldiimidazole, phosgene, diphosgene or triphosgene; The base is potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, sodium amide, potassium amide, sodium (C ₁ -C ₄ ) alkoxide or potassium (C ₁ -C ₄ ) alkoxide; and step (e) In the above, the peptide coupling agent is EE
The method is DQ, EDC, DCC or 1-propanephosphonic acid cyclic anhydride.

A preferred method within the scope of Method S, designated Method T, is that in step (a) the carbonyl equivalent is N, N'-carbonyldiimidazole and the reaction inert solvent is methylene chloride. Is; step (b)
In, the base is potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and the reaction inert solvent is N, N-dimethylformamide, toluene, tetrahydrofuran, or a mixture thereof; step (c) In step (e), the acid is methanesulfonic acid, and the reaction-inert solvent is methylene chloride; in step (d), the reaction-inert solvent is a mixture of acetone and water; The peptide coupling agent is 1-propanephosphonic acid cyclic anhydride, the base is triethylamine, and the reaction inert solvent is ethyl acetate; and in step (f) the standard t-butyloxycarbonyl. A method wherein the group removal conditions include using hydrochloric acid in methanol.

The present invention is particularly applicable to 2-amino-N- {1
(R) -Benzyloxymethyl-2- [1,3-dioxo-8a (S) -pyridin-2-ylmethyl-2-
(2,2,2-Trifluoro-ethyl) -hexahydro-imidazo [1,5-a] pyrazin-7-yl] -2-
It is directed to method T for making oxo-ethyl} -2-methyl-propionamide.

[0069]

The preparation of the intermediates of the formula I according to the invention can easily be carried out as explained below. The methods of the present invention for making the compounds of formulas I, II and VI, for example, are also described in detail below.

In the structural formulas disclosed throughout the specification and claims, the following terms have the indicated meanings, unless explicitly stated otherwise. Alkyl groups are intended to include alkyl groups of the specified length, in the form of straight or branched chains, which may contain one or more double or triple bonds. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, te.
r-Butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, ethynyl, propenyl, butadienyl, hexenyl and the like.

When the definition C ₀ -alkyl appears in this definition, it means a single covalent bond. Alkoxy groups specified above are intended to include alkoxy groups having the specified length, in straight or branched chain form, which may contain one or more double or triple bonds. There is. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy,
Isopentoxy, hexoxy, isohexoxy, allyloxy, 2-propynyloxy, isobutenyloxy,
Hexenyloxy and the like.

The term "halogen" or "halo" refers to
Halogen atom Fluorine (F), Chlorine (Cl), Bromine (B
r) and iodine (I) are intended to be included.
The term "alkyl halide" is intended to include alkyl groups as defined above which are substituted with one or more halogen atoms as defined above.

The term "cycloalkyl halide" is intended to include cycloalkyl groups that are substituted with one or more halogen atoms as defined above.
The term "aryl" means phenyl, naphthyl, an aromatic 5-membered ring having 1 to 4 heteroatoms, an aromatic 6-membered ring having 1 to 4 heteroatoms and a nitrogen, sulfur or oxygen heteroatom 1 It is intended to include fused 5 and / or 6 membered bicyclic rings having from 4 to 4 members. Examples of such heterocyclic aromatic rings are:
Pyridine, thiophene, furan, benzothiophene, tetrazole, indole, N-methylindole, dihydroindole, indazole, N-formylindole, benzimidazole, thiazole, pyrimidine, and thiadiazole.

The term "carbonyl equivalent" means a compound containing two leaving groups attached directly to a carbonyl moiety. When a carbonyl equivalent reacts with two nucleophiles, the nucleophiles displace both leaving groups,
A carbonyl group is inserted between the two nucleophiles. Preferred carbonyl equivalents include carbonyldiimidazole, phosgene, diphosgene and triphosgene. A particularly preferred carbonyl equivalent is carbonyldiimidazole.

The term "preformed isocyanate" means an isocyanate used as a reagent, as opposed to an isocyanate formed in situ.
An example of a preformed isocyanate is methyl isocyanate.

The following abbreviations are used herein with the following meanings: Boct-butyloxycarbonyl CBZ benzyloxycarbonyl CDI N, N'-carbonyldiimidazole DCC dicyclohexylcarbodiimide DMF N, N-dimethylformamide EEDQ 2 -Ethoxy-1-ethoxycyclocarbonyl-1,2-dihydroquinoline EDC 1- (3-dimethylaminopropyl)-
3-Ethylcarbodiimide Hydrochloride EtOAc Ethyl acetate FMOC 9-Fluorenylmethoxycarbonyl Hex Hexane HPLC High performance liquid chromatography Hz Hertz KHMDS Potassium bis (trimethylsilyl) amide MHz Megahertz MS Mass spectrum MTBE tert-Butyl methyl ether NMR Nuclear magnetic resonance PPAA 1 -Propanephosphonic Acid Cyclic Anhydride THF Tetrahydrofuran Certain of the terms defined above may occur multiple times in the various structural formulas described herein. For each occurrence, such terms should be defined independently of the others. General Synthesis The method of the present invention is readily performed as described below.

Scheme 1

[0078]

[Chemical 41]

According to Scheme 1, a compound of formula III in which Pt is an amine protecting group and R ² is as defined above is of formula 1-1 in which R ³ is (C ₁ -C ₄ ) alkyl It can be produced from piperazine-2-carboxylic acid ester. For example, ethyl piperazine-2-carboxylic acid ester is protected with a suitable amine protecting group under standard conditions known to those skilled in the art to form a compound of formula IV wherein R ³ is ethyl, which is a preformed isocyanate. Or the formula R
Reaction with amines and carbonyl equivalents of ^2- NH ₂ such as carbonyldiimidazole, phosgene, diphosgene or triphosgene to produce compounds of formula III.

Any amine protecting group known to one of ordinary skill in the art of peptide chemistry can be used to protect the 4-position of the piperazine ring according to Scheme 1. Among these protecting groups, Boc is preferably used because of its stability against subsequent reaction conditions. For example, protection of the 4-amino group of ethylpiperazine-2-carboxylate with Boc can be done according to procedures known to those skilled in the art. For example, ethyl piperazine-2-carboxylate is a base such as triethylamine, 4-dimethylaminopyridine,
Reaction with di-tert-butyl dicarbonate in the presence of diisopropylethylamine, potassium hydroxide or sodium hydroxide. The reaction can be carried out at a temperature of about 0 ° C. to about 80 ° C. for about 1 hour to about 24 hours. Preferably, protection of the amine is 0 in methylene chloride.
Perform at ℃.

A compound of formula IV is reacted with an amine and carbonyl equivalent of formula R ² —NH ₂ in the presence of a suitable tertiary amine in a reaction inert solvent at a temperature of about 0 ° C. to about 80 ° C. Allow to react for 1 hour to about 72 hours. A suitable reaction inert solvent is methylene chloride. Suitable carbonyl equivalents include carbonyldiimidazole, phosgene, diphosgene and triphosgene. Carbonyldiimidazole is particularly preferred. Suitable tertiary amines include triethylamine and diisopropylethylamine.
Triethylamine is especially preferred. The compound of formula IV may be reacted with an isocyanate such as methylisocyanate in a reaction inert solvent at about room temperature to about 60 ° C. A suitable solvent is refluxing acetone.

Scheme 2

[0083]

[Chemical 42]

According to Scheme 2, the intermediate compound of formula I
It can be prepared from the compound of III. For example, formula III
A compound of formula R ¹ -Z, wherein R ¹ is as defined above and Z is a suitable leaving group, in the presence of a suitable base. A compound of formula I is obtained. Suitable leaving groups include methanesulfonyloxy,
Includes p-toluenesulfonyloxy and halo. In a particularly preferred route, R ¹ -Z is 2-picolyl chloride. Suitable bases include alkaline amides and alkaline (C ₁ -C ₄ ) alkoxides such as sodium ethoxide, sodium methoxide, potassium t-butoxide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide or potassium bis ( Trimethylsilyl) amide. This alkylation reaction is carried out in a reaction inert solvent such as N, N-dimethylformamide, tetrahydrofuran, diethyl ether,
Perform in toluene etc. The reaction is carried out at about -78 ° C to about 25 ° C for about 1 hour to about 24 hours. When the alkylating agent contains a ring nitrogen atom, such as 2-picolyl chloride, it is preferred to use the free base form of the alkylating agent.

After the alkylation is complete, the amine protecting group (Pt) of the compound of formula I is removed by performing deprotection methods known to those skilled in the art. For example, if Pt is CBZ, the CBZ group is removed by catalytic hydrogenation.
An acid such as hydrochloric acid or trifluoroacetic acid can be added to the hydrogenation mixture to ensure completion of the reaction. A palladium catalyst is preferably used in the removal of the CBZ group.

Alternatively, if Pt is the preferred protecting group, Boc, the skilled artisan can treat the compound of formula I with an acid to effect deprotection. Preferred acids for such deprotection include trifluoroacetic acid, methanesulfonic acid and dilute hydrochloric acid. This Boc protected amine has the formula II
A compound of I with methanesulfonic acid in a polar solvent, for example,
About -3 in methanol, ethanol and dichloromethane
Deprotection is preferably by treatment at a temperature of 0 ° C. to about 25 ° C. for about 1 hour to about 24 hours.

The compound of formula V thus prepared is obtained in racemic form. Optical separation of compounds of formula V can be performed according to the procedure described in Scheme 3 to produce compounds of formula X.

Scheme 3

[0089]

[Chemical 43]

According to Scheme 3, a compound of formula V is prepared in a suitable mixed solvent system containing a polar organic solvent and water (eg ketone / water such as acetone / water or alcohol / water such as methanol / water). The compound of formula V is separated into the different optically active enantiomers of formula X by treatment with D-tartaric acid. The resulting diastereomers are separated by methods known to those skilled in the art.

Scheme 4

[0092]

[Chemical 44]

According to Scheme 4, the compound of formula X is converted to the compound of formula XIV
Condensation with a compound of formula XV gives the compound of formula XV. This condensation can be carried out with suitable peptide coupling agents such as EEDQ, E
It is carried out in the presence of DC, DCC or PPAA and a base such as triethylamine or diisopropylethylamine in a reaction inert solvent at a temperature of about -55 ° C to about 0 ° C for about 1/2 hour to about 8 hours. Preferred reaction inert solvents include ethyl acetate, tetrahydrofuran and methylene chloride. Ethyl acetate is especially preferred. P
PAA is a particularly preferred peptide coupling agent.
A particularly preferred base is triethylamine. Typically, the protecting group (P) of formula XIV is Boc, which is as described above or other methods known to those skilled in the art, such as Protecting Groups in Organic Synthesis, Greene.
And Wuts, (John Wiley & Sons, New York, 1991).
It is removed by the method described in 1.

The compound of formula X can be used as its free base in this condensation. The free base form of formula X can be formed by treating a compound of formula X with ammonium hydroxide or aqueous sodium bicarbonate.

Scheme 5

[0096]

[Chemical formula 45]

As shown in Scheme 5, the amino acid of formula 5-1 in which Pt is a suitable protecting group is added to DMF or TH.
Intermediate ethers of formula 5-2 by treatment with a base such as potassium carbonate or sodium hydride, followed by benzyl mesylate, benzyl tosylate or benzyl halide such as benzyl bromide in a suitable solvent such as F. Can be manufactured. Deprotection of this amine converts 5-2 to 5-3.

Scheme 6

[0099]

[Chemical formula 46]

As shown in Scheme 6, the acid of formula 6-1 is treated with hydroxysuccinimide in the presence of a coupling agent such as EDC in an inert solvent such as methylene chloride. -2 intermediate can be prepared. Treatment of 6-2 with an amino acid of formula 5-3 at about room temperature in a solvent such as DMF in the presence of a base such as diisopropylethylamine or triethylamine produces a compound of formula XI.

(C ₁ -C ₄ ) alkylpiperazine-2-carboxylates can be prepared by methods known to those skilled in the art, for example Synthe
It can be synthesized by the method described in sis, 1992, 1065-1066. For example, ethyl piperazine-2-carboxylate can be produced by coupling ethyl 2,3-dibromopropionate and N, N′-dibenzylethylenediamine by a known alkylation method. This reaction is typically carried out in the presence of a base such as triethylamine in a reaction inert solvent at a temperature of about 25 ° C. to about 100 ° C. for about 1 hour to about 24 hours, preferably under nitrogen. To do. A particularly preferred solvent for this reaction is toluene. The N-benzyl group can be removed by hydrogenation to produce the alkylpiperazine-2-carboxylate.

Alternatively, the piperazine-2-carboxylic acid is esterified with ethanol in the presence of a suitable acid catalyst such as sulfuric acid, hydrochloric acid or p-toluenesulfonic acid to form ethylpiperazine-2-carboxylate. According to (C ₁ -C ₄ ) alkylpiperazine-2-
Carboxylates can be produced (e.g., M.
D. Armstrong et al., J. Am. Chem. Soc., 77: 6049-6051; (195
Five)).

The compounds of formula II prepared by the method of the present invention all have at least two asymmetric centers, as shown by the wedge-shaped bonds in this structural formula. Additional asymmetric centers may be present on the molecule depending on the nature of the various substituents on the molecule. Each such asymmetric center gives rise to two optical isomers, all such optical isomers being separated pure or partially purified optical isomers, their racemic mixtures or diastereomers. It is intended to be included in compounds of formula II as a stereomeric mixture.

The compounds of formulas II and VI prepared according to the invention are generally in the form of their pharmaceutically acceptable acid addition salts, for example those salts derived from the use of inorganic and organic acids. Be separated. Examples of such acids are hydrochloric acid, nitric acid, sulfuric acid, phosphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, succinic acid, D-tartaric acid, L-tartaric acid, malonic acid, methanesulfonic acid and the like. is there. In addition, certain compounds containing acidic functional groups such as carboxy can be isolated in the form of their inorganic salts, whose counterions are sodium, potassium, lithium,
In addition to being able to select from calcium, magnesium, etc., it is also possible to select from organic bases.

The pharmaceutically acceptable salts are about 1 equivalent of Formula II
Is formed by contacting it with about 1 equivalent of the appropriate corresponding acid of the desired salt. Work-up and isolation of the resulting acid is known to those skilled in the art.

International application PCT / I commonly assigned
As disclosed in B98 / 00873, the growth hormone secretagogues of formula II produced by the method of the present invention understand how growth hormone secretion is regulated at the pituitary level in vitro. Useful as a unique tool for. As such, the compounds of formula II are useful for all uses described therein and can be administered as described therein. Further, the dose of the compound of formula II can be determined as described therein.

Many protected amino acid derivatives are commercially available and the amine protecting groups are, for example, Boc, CBZ, F
MOC, benzyl or ethoxycarbonyl group. Other protected amino acid derivatives can be prepared by literature methods known to those skilled in the art. Several substituted piperazines and piperidines are commercially available, many other piperazines and 4
-Substituted piperidines are known in the literature. A variety of heterocyclic substituted piperidines and piperazines can be prepared with derivatized heterocyclic intermediates according to literature methods. Alternatively, the heterocycle of such compounds can be derivatized by standard means, such as coupling with CDI, hydrogenation of an aromatic heterocycle, etc., as known to those skilled in the art.

Many of the reactions of the present invention involve amine protecting groups (P
For compounds containing t), the amine protecting group can be any suitable protecting group known to those skilled in the art. The benzyloxycarbonyl group can be removed by several methods, including the presence of a palladium or platinum catalyst,
Included is catalytic hydrogenation with hydrogen in a protic solvent such as methanol. The preferred catalyst is palladium hydroxide on carbon or palladium on carbon. 1-1000
Hydrogen pressure of psi can be used; 10 to 70p
A pressure of si is preferred. Alternatively, the benzyloxycarbonyl group can be removed by rearrangement hydrogenation.

Removal of the Boc protecting group is accomplished using a strong acid such as trifluoroacetic acid, methanesulfonic acid or hydrochloric acid,
It can be carried out in the presence or absence of a co-solvent such as dichloromethane or methanol at a temperature of about -30 ° C to about 70 ° C, preferably about -5 ° C to about 35 ° C.

The benzyl group on the amine can be removed by several methods, including catalytic hydrogenation with hydrogen in a protic solvent such as methanol in the presence of a palladium catalyst. 1-1000ps
Hydrogen pressure of i can be used; 10 to 70 psi
Is preferred. Addition and removal of these and other protecting groups is described in Protective Groups in Organic Synthesis,
T. Green in John Wiley & Sons, New York, 1981.
discussed in detail by e.

[0111]

EXAMPLES General Procedure A: (Cleavage of Boc Protecting Group from Boc Protected Amine with Concentrated HCl): Boc Protected Amine is dissolved in a minimum volume of ethanol to form a solution at about 0 ° C.
The reaction mixture was allowed to warm to room temperature by adding concentrated HCl (typically about 1 to 4 mL per mmol of Boc protected amine) for about 1 hour to about 2.5 hours (or a thin layer). Stir for the time required for complete disappearance of starting material to more polar product as judged by chromatography). The resulting solution or suspension is concentrated and the residue is co-evaporated several times with additional ethanol to give the amine hydrochloride, which is used without further purification or purified as specified.

Example 1 Step 1: Ethyl 1,4-dibenzylpiperazine-2-
Carboxylate To a stirred solution of 2,3-dibromopropionate (142.7 g, 0.549 mol) in dry toluene (2000 mL) was added N, N'-dibenzylethylenediamine (13
2 g, 0.549 mol), then triethylamine (1
10.8 g, 1.098 mol) was added at 40 ° C. under N ₂ (because a dense white precipitate formed immediately,
Good stirring was required). The mixture was heated at 80 ° C. overnight, cooled and filtered. Then, the filtrate is mixed with H ₂ O.
Washed with, dried over MgSO ₄ and concentrated under reduced pressure.
The residual oil was purified without further purification (GC-MS shows one peak at 6.79) or by column chromatography (EtOAc / hexane 1: 4) and passed on to the next step. . Weight of crude product:
169.6 g (91%).

Impurities present in the product are
It is removed by granulating.Step 2: Ethylpiperazine-2-carboxylate Procedure A: Ethyl 1,4-dibenzylpiperazine-2-ca
Ruboxylate (prepared as described in step 1, 3
3.8 g, 0.1 mol) in ethanol (500 mL)
Dissolve 10 equivalents of acetic acid at room temperature and pressure of 50 psi
(60 g) overnight in 10% Pd-C (1
Hydrogenated with 0 g). Celite this mixture ^RPad of
Filtered through to remove the catalyst. The catalyst is ethanol
It was washed with le. Combine the filtrate / washing solution and concentrate to yellow.
I got a color syrup. 50 mL of Et on this yellow syrup
OAc and 50 mL hexane were added. This suspension
Was stirred at room temperature for 1 hour and the resulting white solid was collected by filtration.
To give 24 g (88%) of the title compound.

Procedure B: Ethyl 1,4-dibenzylpiperazine-2-carboxylate (prepared as described in Step 1, 6.929) in dry methanol (120 mL).
g, to a stirred solution of 20.5 mmol), under N _2, 1
0% Pd / C (6.0 g) and anhydrous ammonium formate (10.25 g, 162.5 mmol) were added. The resulting mixture was refluxed under N ₂ for 3 hours. The mixture was filtered through Celite ^R pad to remove the catalyst.
The catalyst was washed with methanol. The filtrate was concentrated to give a yellow syrup. EtOAc 20 in this yellow syrup
3 mL AcOH in 20 mL mL / hexane was added. The white solid that precipitated on stirring was collected by filtration to give 4.85 g (86%) of the title compound. Step 3: Piperazine-1,3-dicarboxylic acid 1-ter
t- butyl ester 3-ethyl ester CH ₂ Cl ₂ (250 mL) solution of di -tert- butyldicarbonate (40.72g, 0.186 mol) in a solution of CH
Prepared by the method described in ₂ Cl ₂ (600 mL) of ethyl piperazine-2-carboxylate (Step 2,
A mixture of 48.69 g, 0.178 mol) and triethylamine (89.74 g, 0.889 mol) was added slowly at 0 ° C. with good stirring. The mixture was stirred overnight. Then the reaction mixture was washed with H ₂ O to remove MgS.
Dry over O ₄ and concentrate to give 43.22 g of crude product (94%). The product was passed to the next step without purification. Step 4: 1,3-dioxo-2- (2,2,2-trif
Luoro-ethyl) -hexahydro-imidazo [1,5-
a] Pyrazine-7-carboxylic acid tert-butyl ester
Le triethylamine (47.60 g, 0.47 mol) C
H ₂ Cl ₂ (800 mL) solution of N, N'-carbonyl diimidazole (65.38g, 0.403 mol) and 2,
2,2-trifluoroethylamine.HCl (63.7
5 g, 0.47 mol) was added to the suspension. The mixture was stirred over the weekend. CH ₂ Cl ₂ (350 m
L) in piperazine-1,3-dicarboxylic acid 1-ter
t-Butyl ester 3-ethyl ester (prepared as described in step 3, 43.22 g, 0.168 mol) was added and the resulting solution was stirred at room temperature for 2 days. The solution was diluted with 250 mL H ₂ O and added to CH ₂ Cl ₂ (3 x 3
50 mL). The product was purified by granulation in hexane to give 57.80 g (100% of the title compound.
%) Was obtained. Step 5: 1,3-dioxo-8a-pyridin-2-yl
Methyl-2- (2,2,2-trifluoro-ethyl)-
Hexahydroimidazo [1,5-a] pyrazine-7-ca
Rubonic acid tert-butyl ester In a flame dried glassware, 1,3-dioxo-2- (2,2
2,2-Trifluoro-ethyl) -hexahydro-imidazo [1,5-a] pyrazine-7-carboxylic acid tert
-Butyl ester (prepared as described in step 4, 1
0.11 g, 30 mmol) DMF 150 mL / T
It was dissolved in 30 mL of HF and cooled to -78 ° C. Potassium bis (trimethylsilyl) amide (KHMDS, 0.
5M solution, 90 mL, 45 mmol) was added dropwise and stirred at -78 ° C for 1 hour. 2-Picolyl chloride.HCl (14.76 g, 90 mmol) was reacted with saturated aqueous NaHCO ₃ solution (150 mL) in another glassware and extracted with CH ₂ Cl ₂ (3 × 150 mL), MgSO 4.
Dried at ₄ , 50 mL dry THF was added along with some molecular sieves. The resulting solution of 2-picolyl chloride free base was added to the reaction mixture via syringe at -78 ° C and allowed to warm to room temperature overnight. Toluene and THF
Was evaporated and the resulting DMF solution was added with 150 mL of H ₂ O.
/ IPE was distributed in 150 mL. 1,4-diazabicyclo [2,2,2] octane (7.3 g, 65 mmol) and K ₂ CO ₃ to (12 g, 90 mmol) was added to this solution, the excess solution was stirred for 1 hour chloride 2-picolyl was removed. The organic solvent is separated and it is removed by evaporation to give essentially pure title compound 11.45 g.
(89%) was obtained. Step 6: 8a-pyridin-2-ylmethyl-2- (2,
2,2-trifluoro-ethyl) -tetrahydro-imi
Dazo [1,5a] pyrazine-1,3-dione 1,3-dioxo -8a- in CH ₂ Cl ₂ (20 mL)
Pyridin-2-ylmethyl-2- (2,2,2-trifluoro-ethyl) -hexahydro-imidazo [1,5-
a] pyrazine-7-carboxylic acid tert-butyl ester (prepared as described in step 5 1.89 g, 4.
4 mmol) in a solution of MeSO ₃ H (2.14 g, 22
Mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Triethylamine (2.45 g, 24.2 mmol) was added to this solution. The organic layer was washed with 100 mL H ₂ O, brine, dried over MgSO ₄ and concentrated to give 1.4 g of the title compound as a yellow oil (97).
%). The oil was solidified by granulating in hexane or by cooling. Step 7: 8a (S) -pyridin-2-ylmethyl-2-
(2,2,2-Trifluoro-ethyl) -tetrahydro
-Imidazo [1,5-a] pyrazine-1,3-dione Acetone (2120 mL) and 8 in water (212 mL).
a-Pyridin-2-ylmethyl-2- (2,2,2-trifluoro-ethyl) -tetrahydro-imidazo [1,
5a] Pyrazine-1,3-dione (prepared by the method described in step 6, 106 g, 0.325 mol) was added D-tartaric acid (48.46 g, 0.325 mol). A white precipitate formed, which was granulated for 3 hours.
These solids were collected by suction filtration and washed with acetone. The solvent wet solid was placed in acetone (1000 mL) and stirred at 56 ° C. overnight. These solids were collected by suction filtration the next morning and dried to give 56 g of the title chiral compound.
Was obtained as the D-tartrate salt (yield of 73% of theory). Chiral HPLC showed an optical purity of 98: 2.

This tartrate salt was treated with saturated NaH in EtOAc.
Free-basification by stirring with CO ₃ gave a yield of 96%. Step 8: (1- (1 (R) -benzyloxymethyl-2
-(1,3-dioxo-8a (S) -pyridin-2-i
Lumethyl-2 (2,2,2-trifluoro-ethyl)-
Hexahydro-imidazo [1,5-a] pyrazine-7-
Yl) -2-oxo-ethylcarbamoyl) -1-methyi
Ru-ethyl-carbamic acid tert-butyl ester The title compound of step 7 in ethyl acetate (10.0 g, 3
0.5 mmol) and the title compound of Preparation 2 (13.9
g, 36.6 mmol) at 0 ° C., triethylamine (17 mL, 122 mmol) was added, followed by addition of 50 of 1-propanephosphonic acid cyclic anhydride in ethyl acetate.
% Solution (18.1 mL, 30.5 mmol) was added slowly to warm the reaction to room temperature. After about 15 hours, the reaction was extracted with ethyl acetate from saturated sodium bicarbonate,
The combined organics were washed with water and dried and brine (MgSO _4), concentrated in vacuo, using a methanol The product 1% 0% in chloroform, and to 5% as eluent Purification by silica gel chromatography gave the title compound (19.5 g, 92%) as a colorless foam. Step 9: 2-Amino-N- (1 (R) -benzyloxy
Methyl-2- (1,3-dioxo-8a (S) -pyridy
N-2-ylmethyl-2- (2,2,2-trifluoro
-Ethyl) -hexahydro-imidazo [1,5-a] pi
Radizin-7-yl) -2-oxo-ethyl) -2-methyi
Le-propionamide, hydrochloride The title compound of step 8 (17.5 g, 25.3 mmol) was deprotected by the method described in general procedure A,
A colorless solid was obtained. The product was triturated with diethyl ether to give the title compound. (13.6 g, 90%):
+ APcl MS (M + H) ⁺ 591.

Production Example 1 2-tert-butoxycarbonylamino-2-methyl
-Propionic acid 2,5-dioxo-pyrrolidin-1-y
Glycol ester in anhydrous dichloromethane (1.4 L) solution of N- hydroxysuccinimide (112 g, 0.973 mol), N-t-
Butoxycarbonyl-α-methylalanine (197 g,
0.969 mol), and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide (186 g, 0.
A stirred solution of (970 mol) was stirred at room temperature for about 18 hours under a nitrogen atmosphere. The reaction mixture was washed three times with saturated sodium bicarbonate solution, then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound of Preparation 1 as a white solid (256g, 88%): PBMS (M + 18) ⁺ 31.
8: ¹ H NMR = 250 MHz (CDCl ₃ ) δ: 4.
91 ( NH , brs, 1H), 2.84 (-CO (C
_{H 2) 2 CO-, s,} 4H), 1.67 (Me, s, 6
H), 1.48 (BOC, s, 9H).

Production Example 2 3-benzyloxy-2- (2-tert-butoxyca)
Rubonylamino-2-methyl-propionylamino)-
Propionic acid D-O- in water / dioxane (250/1000 mL)
To a solution of benzylserine (106 g, 0.532 mol) and the title compound of Preparation 1 (160 g, 0.532 mol) was added triethylamine (223 mL, 1.60 mol) slowly at room temperature. The reaction was heated to about 50 ° C. under a nitrogen atmosphere and stirred for about 15 hours. Then the solvent was removed in vacuo, ethyl acetate was added and the stirred mixture was acidified to pH 2-3 with 10% aqueous HCl.
The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound of Preparation 2 (200 g, 9
9%): - APcl MS ( M-1) - 379; 1 H N
MR = 300 MHz (methanol-d ₄ ) δ: 7.69
( NH , d, 1H), 7.32 (Ph, m, 5H),
4.60 (C H CO ₂ H, m, 1H), 4.51 (C H ₂
Ph, s, 2H), 3.81 (C H ₂ OBz, m, 2
H), 1.41 (Me, s, 6H), 1.40 (BO
C, s, 9H).

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor David Andrew Griffith             06475, Connecticut, United States             Sardbrook, Burley Hill             Road 10 F-term (reference) 4C050 AA01 BB05 CC08 EE03 FF10                       GG03 HH04

Claims (40)

[Claims] 1. A compound of formula VII: [Chemical 1] (Here, Pt is an amine protecting group.) 2. The compound according to claim 1, wherein Pt is Boc. 3. A method for producing a compound of formula III: [Chemical 2] (here, Pt is an amine protecting group; R²Is hydrogen, (C₁-C₈)
Alkyl,-(C₀-C₃) Alkyl- (C₃-C₈) Shiku
Lower alkyl,-(C₁-C_Four) Alkyl-A¹Or A¹And
R; each A¹Is (C_Five-C₇) Cycloalkenyl: F
Phenyl: independently selected from the group consisting of oxygen, sulfur and nitrogen
May have 1 to 4 heteroatoms selected
Partially saturated, fully saturated, or completely unsaturated
Consisting of nitrogen, sulfur and oxygen
1 to 4 heteroatoms independently selected from the group
May have partially saturated, fully saturated, if
Fused to a fully unsaturated 5- or 6-membered ring,
Independently selected from the group consisting of nitrogen, sulfur and oxygen
Partly optionally having 1 to 4 heteroatoms
5 saturated, fully unsaturated, or completely saturated
Independently selected from the group consisting of 6-membered bicyclic ring systems.
Selected; each A¹Is A¹Is a bicyclic ring system
One ring or, in some cases, both rings up to three
It may be independently substituted with a substituent, and each substituent is
F, Cl, Br, I, OCF₃, OCF₂H, CF₃, C
H₃, OCH₃, -OX⁶, -C (O) N (X⁶)
(X⁶), -C (O) OX⁶, Oxo, (C₁-C₆) Al
Kill, nitro, cyano, benzyl, -S (O)_m(C₁−
C₆) Alkyl, 1H-tetrazol-5-yl, phenyl
Phenoxy, phenylalkyloxy, halopheni
, Methylenedioxy, -N (X⁶) (X⁶), -N (X
⁶) C (O) (X⁶), -S (O)₂N (X⁶) (X⁶),
-N (X⁶) S (O)₂-Phenyl, -N (X⁶) S
(O)₂X⁶, -CONX¹¹X¹², -S (O)₂NX¹¹X
¹², -NX⁶S (O)₂X¹², -NX⁶CONX¹¹X¹²,
-NX⁶S (O)₂NX¹¹X¹², -NX⁶C (O) X¹²,
Group consisting of imidazolyl, thiazolyl and tetrazolyl
More independently selected, but A¹Is methylenedioxy
One methylenedioxy when it may be substituted
Can only be replaced with; where X¹¹Is hydrogen
Or may be substituted (C₁-C₆) Is alkyl
R; X¹¹Which may be substituted as defined for
(C₁-C₆) Alkyl is independently phenyl, phenoxy
Shi, (C₁-C₆) Alkoxycarbonyl, -S (O)_m
(C₁-C₆) Alkyl, 1 to 5 halo groups, 1 not
3 hydroxy groups, 1 to 3 (C₁-C_Ten)
An alkanoyloxy group or 1 to 3 (C₁-C₆)
Optionally substituted with an alkoxy group; X¹²Is hydrogen,
(C₁-C₆) Alkyl, phenyl, thiazolyl, imida
Zolyl, furyl or thienyl, provided that X¹²Is hydrogen
If not X¹²Groups are Cl, F, CH₃, OCH₃,
OCF₃And CF₃1 independently selected from the group consisting of
It may be substituted with 3 substituents; or X¹¹Over
And X¹²Together with-(CH₂)_r-L¹-(CH₂)_rForm-
Done; L¹Is C (X²) (X²), O, S (O)_mOr
N (X²); Each X⁶Independently, hydrogen, substituted
May be (C₁-C₆) Alkyl, (C₂-C₆) Ha
Alkylogenogen, optionally substituted (C₃-C₇)
Cycloalkyl, (C₃-C₇) Halogenated cycloalkyl
And X here⁶Even if replaced in the definition of
Good (C₁-C₆) Alkyl and optionally substituted
(C ₃-C₇) Cycloalkyl is independently (C₁-C_Four)
Alkyl, hydroxy, (C ₁-C_Four) Alkoxy, cal
Boxil, CONH₂, -S (O)_m(C₁-C₆) Archi
Carboxylic acid (C₁-C_Four) Alkyl ester or 1H
-Tetrazol-5-yl mono- or di-substituted
May also; or two X's per atom⁶The group exists and
Both X⁶Independently (C₁-C₆) Is alkyl,
The two (C₁-C₆) Alkyl groups are linked to form a bond between the two
X⁶Together with the atom to which the group is attached, oxygen, sulfur or N
X⁷4 to 9 members which may have as a ring constituent element
May form a ring; each r is independently 1, 2 or
It is 3. ) Compound of formula IV [Chemical 3] (Where R³Is (C₁-C_Four) Alkyl and P
t is as defined above. ) Is preformed
Socyanate or carbonyl equivalent and R²NH₂(here
And R²Is as defined above) and reactive inert
About 1 hour to about 72 hours in a medium, about 0 ° C. to about 80
A method comprising reacting at a temperature of ° C. 4. R ² is hydrogen, (C ₁ -C ₈ ) alkyl or-
(C ₀ -C ₃ ) alkyl- (C ₃ -C ₈ ) cycloalkyl; the alkyl group and cycloalkyl group in the definition of R ² may be substituted with 1, 2 or 3 fluorines, and The method of claim 3, wherein Pt is tert-butyloxycarbonyl. 5. The method of claim 4 wherein the compound of formula IV is reacted with a carbonyl equivalent selected from carbonyldiimidazole, phosgene, triphosgene and diphosgene. 6. The method of claim 5 wherein said carbonyl equivalent is carbonyldiimidazole and said reaction inert solvent is methylene chloride. 7. The method of claim 6 wherein R ² is methyl, ethyl or 2,2,2-trifluoroethyl. 8. The method of claim 7 wherein R ² is methyl. 9. The method of claim 7 wherein R ² is ethyl. 10. The method of claim 7 wherein R ² is 2,2,2-trifluoroethyl. 11. A process for preparing a compound of formula I: [Chemical 4] (here, R¹Is-(CH₂)_qN (X⁶) C (O) X⁶,-(CH₂)
_qN (X⁶) C (O) (CH₂)_t-A¹,-(CH₂)_qN
(X⁶) S (O)₂(CH₂)_t-A¹,-(CH₂)_qN
(X⁶) S (O)₂X⁶,-(CH₂)_qN (X⁶) C (O)
N (X⁶) (CH₂)_t-A¹,-(CH₂)_qN (X⁶) C
(O) N (X⁶) (X⁶),-(CH₂)_qC (O) N (X
⁶) (X⁶),-(CH₂)_qC (O) N (X⁶) (CH₂)
_t-A¹,-(CH₂)_qC (O) OX⁶,-(CH₂)_qC
(O) O (CH₂)_t-A¹,-(CH ₂)_qOX⁶,-(C
H₂)_qOC (O) X⁶,-(CH₂)_qOC (O) (C
H₂)_t-A¹,-(CH₂)_qOC (O) N (X⁶) (CH
₂)_t-A¹,-(CH₂)_qOC (O) N (X⁶)
(X⁶),-(CH₂)_qC (O) X⁶,-(CH₂)_qC
(O) (CH₂)_t-A¹,-(CH₂)_qN (X⁶) C
(O) OX⁶,-(CH₂)_qN (X⁶) S (O)₂N
(X⁶) (X⁶),-(CH₂)_qS (O)_mX⁶,-(CH
₂)_qS (O)_m(CH₂)_t-A¹,-(C₁-C_Ten) Al
Kill,-(CH₂)_q-A¹,-(CH₂) _q-(C₃−
C₇) Cycloalkyl,-(CH₂)_q-Y¹-(C₁−
C₆) Alkyl,-(CH₂)_q-Y¹-(CH₂)_t-A¹
Or- (CH₂)_q-Y¹-(CH₂)_t-(C₃−
C₇) Cycloalkyl; where R¹In the definition of
Alkyl and cycloalkyl groups are (C₁-C_Four) Archi
Le, hydroxy, (C₁-C_Four) Alkoxy, carboxy
Le, -CONH₂, -S (O)_m(C₁-C₆) Alkyl,
-CO₂(C₁-C_Four) Alkyl ester, 1H-tetra
With zol-5-yl or 1, 2 or 3 fluoro groups
Optionally substituted; Y¹Is O, S (O)_m, -C
(O) NX⁶-, -CH = CH-, -C≡C-, -N
(X⁶) C (O)-, -C (O) NX⁶-, -C (O) O
-, -OC (O) N (X⁶)-Or -OC (O)-
Q is 1, 2, 3 or 4; t is 0, 1, 2 or
3; R¹In the definition of (CH₂)_qGroup and (C
H₂)_tThe groups are independently hydroxy, (C₁-C_Four) Arco
Xy, carboxyl, -CONH₂, -S (O)_m(C₁
-C₆) Alkyl, -CO₂(C₁-C_Four) Alkyl Esthe
1, 1H-tetrazol-5-yl, 1, 2 or 3
Or a fluoro group of 1 or 2 (C₁-C_Four) Archi
Optionally substituted with a R group; and R²Is hydrogen, (C₁
-C₈) Alkyl,-(C₀-C₃) Alkyl- (C₃-C
₈) Cycloalkyl,-(C₁-C_Four) Alkyl-A¹Or
A¹And where R¹An alkyl group in the definition of and
Cycloalkyl group is hydroxy, -C (O) OX⁶,-
C (O) N (X⁶) (X⁶), -N (X⁶) (X⁶), -S
(O)_m(C₁-C₆) Alkyl, -C (O) A¹, -C
(O) (X⁶), CF₃, CN or 1, 2 or 3
Optionally substituted with independently selected halo groups; each
Of A¹Is (C_Five-C₇) Cycloalkenyl: phenyl:
Independently selected from the group consisting of oxygen, sulfur and nitrogen
Partly optionally having 1 to 4 heteroatoms
4 saturated, fully saturated, or completely unsaturated
8 membered ring: and from the group consisting of nitrogen, sulfur and oxygen
Having 1 to 4 independently selected heteroatoms
May be partially saturated, fully saturated, or completely
Fused to an unsaturated 5- or 6-membered ring with nitrogen,
1 to independently selected from the group consisting of Au and oxygen
Partially saturated optionally having 4 heteroatoms,
Fully unsaturated or fully saturated 5- or 6-membered
Independently selected from the group consisting of bicyclic ring systems consisting of rings;
Each A¹Is A¹One ring if is a bicyclic ring system
Or, in some cases, both rings have up to 3 substituents
It may be independently substituted, and each substituent is F, C
l, Br, I, OCF₃, OCF₂H, CF₃, CH₃, O
CH₃, -OX⁶, -C (O) N (X⁶) (X⁶), -C
(O) OX⁶, Oxo, (C₁-C₆) Alkyl, nit
B, cyano, benzyl, -S (O)_m(C₁-C₆) Al
Kill, 1H-tetrazol-5-yl, phenyl, pheno
Xy, phenylalkyloxy, halophenyl, methyl
Ndioxy, -N (X⁶) (X⁶), -N (X⁶) C
(O) (X⁶), -S (O)₂N (X⁶) (X⁶), -N
(X⁶) S (O)₂-Phenyl, -N (X⁶) S (O)₂X
⁶, -CONX¹¹X¹², -S (O)₂NX¹¹X¹², -NX
⁶S (O)₂X¹², -NX⁶CONX¹¹X¹², -NX⁶S
(O)₂NX¹¹X¹², -NX⁶C (O) X¹², Imidazori
Independently from the group consisting of thiol, thiazolyl and tetrazolyl
Selected, but A¹Is replaced by methylenedioxy
Optionally substituted with one methylenedioxy
Can only be; here X¹¹Is hydrogen or substituted
May be (C₁-C₆) Alkyl; X¹¹Nitsu
And optionally substituted (C₁-C₆)
Rukyl independently represents phenyl, phenoxy, (C₁−
C₆) Alkoxycarbonyl, -S (O)_m(C₁-C₆)
Alkyl, 1 to 5 halo groups, 1 to 3 hydrs
Roxy group, 1 to 3 (C₁-C_Ten) Alkanoyl
An oxy group or 1 to 3 (C₁-C₆) Alkoxy group
Optionally substituted with; X¹²Is hydrogen, (C₁-C₆)
Rukyl, phenyl, thiazolyl, imidazolyl, furyl
Or thienyl, provided that X¹²Is not hydrogen
Is X¹²Groups are Cl, F, CH₃, OCH₃, OCF₃And C
F₃1 to 3 units independently selected from the group consisting of
Optionally substituted with a substituent; or X¹¹And X¹²Are together
To-(CH₂)_r-L¹-(CH₂)_r-Forms; L¹Is C
(X²) (X²), O, S (O)_mOr N (X²)
R; each X⁶Are independently hydrogen, optionally substituted
I (C₁-C₆) Alkyl, (C₂-C₆) Alkyl halides
Kill, may be replaced (C₃-C₇) Cycloalk
Le, (C₃-C₇) Cycloalkyl halide,
X here⁶May be substituted in the definition of (C₁-C
₆) Alkyl and optionally substituted (C ₃-C₇) Shi
Croalkyl is independently (C₁-C_Four) Alkyl, hydr
Roxy, (C ₁-C_Four) Alkoxy, carboxyl, CO
NH₂, -S (O)_m(C₁-C₆) Alkyl, carboxylic acid
(C₁-C_Four) Alkyl ester or 1H-tetrazole-
Optionally mono- or di-substituted with 5-yl; or 1
2 Xs per atom⁶A group exists and both X⁶Is independent
To (C₁-C₆) Alkyl, the two (C₁−
C₆) The alkyl group is bonded to form the two X⁶Groups are bound
Oxygen, sulfur or NX with atoms⁷The ring component
May form a 4- to 9-membered ring which may have
Each r is independently 1, 2 or 3;
X²Are independently hydrogen or optionally substituted (C₁-C
₆) Alkyl or optionally substituted (C₃-C₇) Shi
A chloroalkyl, where X²Is replaced in the definition of
May be (C₁-C₆) Alkyl and substituted
May be (C₃-C₇) Cycloalkyl is independently -S
(O)_m(C₁-C₆) Alkyl, -C (O) OX³1
5 halo groups or 1-3 OXs³Substituted with a group
May be included; each X³Are independently hydrogen or (C₁
-C₆) Alkyl; X⁷Is hydrogen or hydroxy
May be substituted (C₁-C₆) Alkyl; each
Each m is independently 0, 1 or 2; provided that X is⁶
And X⁷Is C (O) X⁶, C (O) X¹², S (O)₂X⁶
Or S (O)₂X¹²In the form of C (O) or S (O)₂Tied to
Cannot be hydrogen when combined; and Pt is an amine
It is a protecting group. ) Compound of formula III [Chemical 5] (Where Pt and R²Is as defined above
It ) Is the formula R¹-Z (where R¹Is as defined above
And Z is a leaving group. ) Alkylating agent,
Reacted in the presence of a suitable base and reaction inert solvent.
A method that includes letting. 12. R ¹ is-(CH ₂ ) _q --A ¹ or (C _1- ).
C ₇ ) alkyl; and R ² is hydrogen, (C ₁ -C ₈ ) alkyl or — (C ₀ -C ₃ ) alkyl- (C ₃ -C ₈ ) cycloalkyl; where R ² 12. The method of claim 11 wherein the alkyl and cycloalkyl groups in the definition may be substituted with 1, 2 or 3 fluorines and Pt is tert-butyloxycarbonyl. 13. Z in said alkylating agent is p-toluenesulfonyloxy, methanesulfonyloxy or halo; said base is an alkali metal bis (trimethylsilyl) amide or alkali alkoxide; and said reaction inert solvent is N. , N-dimethylformamide, tetrahydrofuran, toluene, isopropyl ether, MTBE or a mixture thereof. 14. R ¹ is —CH ₂ —A ¹ , Z is Cl,
Br or I, and optionally R ² is substituted with hydrogen or 1, 2 or 3 fluoro groups (C ₁ -C ₃₎ The method of claim 13 is alkyl. 15. A ¹ is phenyl, pyridyl or thiazolyl optionally substituted with 1 to 3 substituents, each substituent being F, Cl, CH ₃ , OCF ₂ H, OC.
Independently selected from the group consisting of F ₃ and CF ₃ ; and R ²
15. The method of claim 14, wherein is methyl, ethyl or 2,2,2-trifluoroethyl. 16. R ¹⁵ is pyridin-2-ylmethyl or benzyl, which may be substituted with up to 2 fluoro, chloro or trifluoromethyl; and R ² is methyl. the method of. 17. R¹Is pyridin-2-ylmethyl or
And the benzyl has up to 2 fluoro,
Optionally substituted with loro or trifluoromethyl;
And R ²The method of claim 15, wherein is ethyl. 18. R¹Is pyridin-2-ylmethyl or
And the benzyl has up to 2 fluoro,
Optionally substituted with loro or trifluoromethyl;
And R ²Is 2,2,2-trifluoroethyl
Item 15 method. 19. A method for producing a compound of formula V: [Chemical 6] (here, R¹Is-(CH₂)_qN (X⁶) C (O) X⁶,-(CH₂)
_qN (X⁶) C (O) (CH₂)_t-A¹,-(CH₂)_qN
(X⁶) S (O)₂(CH₂)_t-A¹,-(CH₂)_qN
(X⁶) S (O)₂X⁶,-(CH₂)_qN (X⁶) C (O)
N (X⁶) (CH₂)_t-A¹,-(CH₂)_qN (X⁶) C
(O) N (X⁶) (X⁶),-(CH₂)_qC (O) N (X
⁶) (X⁶),-(CH₂)_qC (O) N (X⁶) (CH₂)
_t-A¹,-(CH₂)_qC (O) OX⁶,-(CH₂)_qC
(O) O (CH₂)_t-A¹,-(CH ₂)_qOX⁶,-(C
H₂)_qOC (O) X⁶,-(CH₂)_qOC (O) (C
H₂)_t-A¹,-(CH₂)_qOC (O) N (X⁶) (CH
₂)_t-A¹,-(CH₂)_qOC (O) N (X⁶)
(X⁶),-(CH₂)_qC (O) X⁶,-(CH₂)_qC
(O) (CH₂)_t-A¹,-(CH₂)_qN (X⁶) C
(O) OX⁶,-(CH₂)_qN (X⁶) S (O)₂N
(X⁶) (X⁶),-(CH₂)_qS (O)_mX⁶,-(CH
₂)_qS (O)_m(CH₂)_t-A¹,-(C₁-C_Ten) Al
Kill,-(CH₂)_q-A¹,-(CH₂) _q-(C₃−
C₇) Cycloalkyl,-(CH₂)_q-Y¹-(C₁−
C₆) Alkyl,-(CH₂)_q-Y¹-(CH₂)_t-A¹
Or- (CH₂)_q-Y¹-(CH₂)_t-(C₃−
C₇) Cycloalkyl; where R¹In the definition of
Alkyl and cycloalkyl groups are (C₁-C_Four) Archi
Le, hydroxy, (C₁-C_Four) Alkoxy, carboxy
Le, -CONH₂, -S (O)_m(C₁-C₆) Alkyl,
-CO₂(C₁-C_Four) Alkyl ester, 1H-tetra
With zol-5-yl or 1, 2 or 3 fluoro groups
Optionally substituted; Y¹Is O, S (O)_m, -C
(O) NX⁶-, -CH = CH-, -C≡C-, -N
(X⁶) C (O)-, -C (O) NX⁶-, -C (O) O
-, -OC (O) N (X⁶)-Or -OC (O)-
Q is 1, 2, 3 or 4; t is 0, 1, 2 or
3; R¹In the definition of (CH₂)_qGroup and (C
H₂)_tThe groups are independently hydroxy, (C₁-C_Four) Arco
Xy, carboxyl, -CONH₂, -S (O)_m(C₁
-C₆) Alkyl, -CO₂(C₁-C_Four) Alkyl Esthe
1, 1H-tetrazol-5-yl, 1, 2 or 3
Or a fluoro group of 1 or 2 (C₁-C_Four) Archi
Optionally substituted with a R group; and R²Is hydrogen, (C₁
-C₈) Alkyl,-(C₀-C₃) Alkyl- (C₃-C
₈) Cycloalkyl,-(C₁-C_Four) Alkyl-A¹Or
A¹And where R¹An alkyl group in the definition of and
Cycloalkyl group is hydroxy, -C (O) OX⁶,-
C (O) N (X⁶) (X⁶), -N (X⁶) (X⁶), -S
(O)_m(C₁-C₆) Alkyl, -C (O) A¹, -C
(O) (X⁶), CF₃, CN or 1, 2 or 3
Optionally substituted with independently selected halo groups; each
Of A¹Is (C_Five-C₇) Cycloalkenyl: phenyl:
Independently selected from the group consisting of oxygen, sulfur and nitrogen
Partly optionally having 1 to 4 heteroatoms
4 saturated, fully saturated, or completely unsaturated
8 membered ring: and from the group consisting of nitrogen, sulfur and oxygen
Having 1 to 4 independently selected heteroatoms
May be partially saturated, fully saturated, or completely
Fused to an unsaturated 5- or 6-membered ring with nitrogen,
1 to independently selected from the group consisting of Au and oxygen
Partially saturated optionally having 4 heteroatoms,
Fully unsaturated or fully saturated 5- or 6-membered
Independently selected from the group consisting of bicyclic ring systems consisting of rings;
Each A¹Is A¹One ring if is a bicyclic ring system
Or, in some cases, both rings have up to 3 substituents
It may be independently substituted, and each substituent is F, C
l, Br, I, OCF₃, OCF₂H, CF₃, CH₃, O
CH₃, -OX⁶, -C (O) N (X⁶) (X⁶), -C
(O) OX⁶, Oxo, (C₁-C₆) Alkyl, nit
B, cyano, benzyl, -S (O)_m(C₁-C₆) Al
Kill, 1H-tetrazol-5-yl, phenyl, pheno
Xy, phenylalkyloxy, halophenyl, methyl
Ndioxy, -N (X⁶) (X⁶), -N (X⁶) C
(O) (X⁶), -S (O)₂N (X⁶) (X⁶), -N
(X⁶) S (O)₂-Phenyl, -N (X⁶) S (O)₂X
⁶, -CONX¹¹X¹², -S (O)₂NX¹¹X¹², -NX
⁶S (O)₂X¹², -NX⁶CONX¹¹X¹², -NX⁶S
(O)₂NX¹¹X¹², -NX⁶C (O) X¹², Imidazori
Independently from the group consisting of thiol, thiazolyl and tetrazolyl
Selected, but A¹Is replaced by methylenedioxy
Optionally substituted with one methylenedioxy
Can only be; here X¹¹Is hydrogen or substituted
May be (C₁-C₆) Alkyl; X¹¹Nitsu
And optionally substituted (C₁-C₆)
Rukyl independently represents phenyl, phenoxy, (C₁−
C₆) Alkoxycarbonyl, -S (O)_m(C₁-C₆)
Alkyl, 1 to 5 halo groups, 1 to 3 hydrs
Roxy group, 1 to 3 (C₁-C_Ten) Alkanoyl
An oxy group or 1 to 3 (C₁-C₆) Alkoxy group
Optionally substituted with; X¹²Is hydrogen, (C₁-C₆)
Rukyl, phenyl, thiazolyl, imidazolyl, furyl
Or thienyl, provided that X¹²Is not hydrogen
Is X¹²Groups are Cl, F, CH₃, OCH₃, OCF₃And C
F₃1 to 3 units independently selected from the group consisting of
Optionally substituted with a substituent; or X¹¹And X¹²Are together
To-(CH₂)_r-L¹-(CH₂)_r-Forms; L¹Is C
(X²) (X²), O, S (O)_mOr N (X²)
R; each X⁶Are independently hydrogen, optionally substituted
I (C₁-C₆) Alkyl, (C₂-C₆) Alkyl halides
Kill, may be replaced (C₃-C₇) Cycloalk
Le, (C₃-C₇) Cycloalkyl halide,
X here⁶May be substituted in the definition of (C₁-C
₆) Alkyl and optionally substituted (C ₃-C₇) Shi
Croalkyl is independently (C₁-C_Four) Alkyl, hydr
Roxy, (C ₁-C_Four) Alkoxy, carboxyl, CO
NH₂, -S (O)_m(C₁-C₆) Alkyl, carboxylic acid
(C₁-C_Four) Alkyl ester or 1H-tetrazole-
Optionally mono- or di-substituted with 5-yl; or 1
2 Xs per atom⁶A group exists and both X⁶Is independent
To (C₁-C₆) Alkyl, the two (C₁−
C₆) The alkyl group is bonded to form the two X⁶Groups are bound
Oxygen, sulfur or NX with atoms⁷The ring component
May form a 4- to 9-membered ring which may have
Each r is independently 1, 2 or 3;
X²Are independently hydrogen or optionally substituted (C₁-C
₆) Alkyl or optionally substituted (C₃-C₇) Shi
A chloroalkyl, where X²Is replaced in the definition of
May be (C₁-C₆) Alkyl and substituted
May be (C₃-C₇) Cycloalkyl is independently -S
(O)_m(C₁-C₆) Alkyl, -C (O) OX³1
5 halo groups or 1-3 OXs³Substituted with a group
May be included; each X³Are independently hydrogen or (C₁
-C₆) Alkyl; X⁷Is hydrogen or hydroxy
May be substituted (C₁-C₆) Alkyl; each
Each m is independently 0, 1 or 2; provided that X is⁶
And X⁷Is C (O) X⁶, C (O) X¹², S (O)₂X⁶
Or S (O)₂X¹²In the form of C (O) or S (O)₂Tied to
When combined, it cannot be hydrogen. ) A compound of the following formula I
object [Chemical 7] (Where Pt is an amine protecting group and R¹And R²
Is as defined above. ) In the presence of an inert solvent
A method comprising reacting with an acid under ambient conditions. 20. R ¹ is-(CH ₂ ) _q -A ¹ or (C _1- ).
C ₇ ) alkyl; and R ² is hydrogen, (C ₁ -C ₈ ) alkyl or — (C ₀ -C ₃ ) alkyl- (C ₃ -C ₈ ) cycloalkyl; where R ² 20. The method of claim 19 wherein the alkyl and cycloalkyl groups in the definition may be substituted with 1, 2 or 3 fluorines and Pt is t-butyloxycarbonyl. 21. The method of claim 20, wherein the acid is methanesulfonic acid and the reaction inert solvent is methylene chloride. 22. R ¹ is —CH ₂ —A ¹ ; and R ² is hydrogen or (C ₁ -C ₃ ) alkyl optionally substituted with 1, 2 or 3 fluoro groups. Item 21. 23. R¹Is -CH₂-A¹And where A¹Is
Phenyl optionally substituted with 1 to 3 substituents
Or pyridyl or thiazolyl, each substituent being
F, Cl, CH₃, OCF₂H, OCF₃And CF₃Empty
Independently selected from the group; and R ²Is methyl, ethyl or
23 is 2,2,2-trifluoroethyl.
Method. 24. R¹Is pyridin-2-ylmethyl or
And the benzyl is up to two fluoro,
Optionally substituted with loro or trifluoromethyl;
And R ²24. The method of claim 23, wherein is methyl. 25. The method of claim 24, wherein said benzyl is optionally substituted with up to 2 fluoros. 26. The method of claim 25, wherein R ¹ is benzyl. 27. The method of claim 25, wherein R ¹ is pyridin-2-ylmethyl. 28. R¹Is pyridin-2-ylmethyl or
And the benzyl is up to two fluoro,
Optionally substituted with loro or trifluoromethyl;
And R ²The method of claim 23, wherein is ethyl 29. The method of claim 28, wherein R ¹ is benzyl. 30. The method of claim 28, wherein R ¹ is pyridin-2-ylmethyl. 31. R¹Is pyridin-2-ylmethyl or
And the benzyl is up to two fluoro,
Optionally substituted with loro or trifluoromethyl;
And R ²Is 2,2,2-trifluoroethyl
Item 23. 32. The method of claim 31, wherein R ¹ is benzyl. 33. The method of claim 31, wherein R ¹ is pyridin-2-ylmethyl. 34. A method for producing a compound of formula XIII: (A) Piperazine-1,3-dicarboxylic acid 1-tert
A butyl ester 3- (C ₁ -C ₄ ) alkyl ester is reacted with a carbonyl equivalent and 2,2,2-trifluoroethylamine in the presence of a reaction inert solvent to form a compound of formula XIV: Chemical 9] (B) The compound of formula XIV is treated with 2-picolyl-Z ¹ (wherein Z ¹ is halo, in the presence of a base and a reaction inert solvent).
It is methanesulfonyloxy or p-toluenesulfonyloxy. ) To form a compound of formula XV below, and (C) reacting the compound of formula XV with an acid in the presence of a reaction inert solvent. 35. In step (a), the carbonyl equivalent is N, N′-carbonyldiimidazole, phosgene, diphosgene or triphosgene, and the reaction inert solvent is methylene chloride; , The alkylating agent is 2-picolyl chloride, and the base is potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, sodium amide, potassium amide, sodium (C ₁ -C ₄ ) alkoxide or potassium (C ₁ -C ₄₎ is an alkoxide,
And the reaction inert solvent is tetrahydrofuran and N,
A mixed solution of N-dimethylformamide; and in the step (c), the acid is methanesulfonic acid,
And the reaction inert solvent is methylene chloride.
Method 4 36. The method of claim 35, wherein in step (a) the carbonyl equivalent is N, N'-carbonyldiimidazole; and in step (b) the acid is potassium bis (trimethylsilyl) amide. Method. 37. A method for producing a compound of formula VI: (A) a compound of the following formula IV: (Where Pt is an amine protecting group and R ³ is (C ₁
-C ₄₎ alkyl. ) Is reacted with a carbonyl equivalent and CF ₃ CH ₂ NH ₂ in a reaction inert solvent to give a compound of formula V
Forming a compound of II, (Here, Pt is as defined above.) (B)
The compound of formula VII is treated with 2-picolyl-Z ¹ (wherein Z ¹ is halo, methanesulfonyloxy or p-toluenesulfonyloxy) at about −78 ° C. in the presence of a base and a reaction inert solvent. To about 25 ° C at about 1
Reacting for a period of time to about 24 hours to form a compound of formula VIII: (C) reacting the compound of formula VIII with a suitable acid in a reaction inert solvent at a temperature of about -30 ° C to about 25 ° C for about 1 hour to about 10 hours to form a compound of formula IX: , (D) separating the compound of formula IX with D-tartaric acid in a reaction inert solvent to form the D-tartrate salt of compound of formula X below: (E) adding the D-tartrate salt of the compound of formula X to a compound of formula XI: (Where Boc is tert-butyloxycarbonyl). Reacting with a peptide coupling agent and a base to form a compound of formula XII: And (f) reacting the compound of formula XII under standard t-butyloxycarbonyl group removal conditions to form a compound of formula VI: A method that includes that. 38. In step (a) said carbonyl equivalent is N, N'-carbonyldiimidazole, phosgene, diphosgene or triphosgene; in step (b) said base is potassium bis (trimethylsilyl).
Amide, sodium bis (trimethylsilyl) amide,
Sodium amide, potassium amide, sodium (C ₁
-C ₄₎ be an alkoxide or potassium (C ₁ -C ₄₎ alkoxide; and in step (e), said peptide coupling agent is EEDQ, EDC, DCC or 1-
38. The method of claim 37, which is a propanephosphonic acid cyclic anhydride. 39. In step (a) the carbonyl equivalent is N, N′-carbonyldiimidazole and the reaction inert solvent is methylene chloride; in step (b) the base is potassium bis. (Trimethylsilyl) amide, sodium bis (trimethylsilyl)
An amide, and the reaction-inert solvent is N, N-dimethylformamide, toluene, tetrahydrofuran, or a mixture thereof; in step (c), the acid is methanesulfonic acid, and the reaction-inert solvent. Is methylene chloride; in step (d), the reaction inert solvent is a mixture of acetone and water; in step (e), the peptide coupling agent is 1-propanephosphonic acid cyclic anhydride; 39. The base is triethylamine and the reaction inert solvent is ethyl acetate; and in step (f) the standard t-butyloxycarbonyl group removal conditions include using hydrochloric acid in methanol. the method of. 40. 2-Amino-N- {1 (R) -benzyloxymethyl-2- [1,3-dioxo-8a (S)-
Pyridin-2-ylmethyl-2- (2,2,2-trifluoro-ethyl) -hexahydro-imidazo [1,5-
a] Pyrazin-7-yl] -2-oxo-ethyl} -2
40. The method of claim 39 for producing -methyl-propionamide.